Considerable evidence indicates that the ingestion of a high-fat (HF) diet predisposes humans and animals to obesity. The applicants hypothesize that: (1) apolipoprotein A-IV (apo A-IV) is an endogenous signal for fat absorption by gastrointestinal apo A-IV production and secretion in response to lipids in the gastrointestinal tract; (2) chronic high-fat diets alter the metabolism of chylomicron (CM) by altering its physiochemical nature; and (3) chronic consumption of a high-fat diet increases the secretion and/or action of intestinal factors that facilitate fat absorption and predispose the body to increase the storage of fat in adipose tissue. SPECIFIC AIM 1. The applicants will determine the dose-response relationship between the dose of lipid fed and the mRNA levels, synthesis and secretion of apo A-IV by the jejunum in animals fed chronically HF compared to low-fat (LF). They will also compare the A-IV response to lipid feeding in jejunum and in ileum and also the type of fat. In addition, they will determine if apo A-IV may be involved in the long-term regulation of food intake and body weight regulation. Specifically, they will use the apo A-IV knockout and transgenic mouse to address this question. SPECIFIC AIM 2. The applicants will test the hypothesis that chronic HF diets alter the metabolism of CM by studying the plasma removal of both the labeled triglyceride and cholesterol ester moieties of the chylomicron (CM) from the HF and LF animals. SPECIFIC AIM 3. The applicants recently discovered that the small intestine secretes glucose in response to a lipid meal and that the glucose concentration in lymph is directly proportional to the amount of lipid transported by the small intestine (r = +0.97). They will test the hypothesis that the gut secretes glucose during lipid absorption and that the gut and/or the lymphatic ducts detect this intestinally-derived de novo glucose. They further hypothesize that the amount of glucose acts as a signal indicating the amount of fat being transported by the small intestine. A corollary hypothesis is that the amount of glucose synthesized and released per unit of fat absorbed, or else the impact of this glucose signaling, is altered by high-fat feeding. In addition, the apo A-IV knockout and transgenic animals will be used to determine if there is interaction between the lymph glucose and lymph apo A-IV signals.